title: Turn up the power - pharmacological activation of mitochondrial biogenesis in mouse models.
abstract: The oxidative phosphorylation (OXPHOS) system in mitochondria is responsible for the generation of the majority of cellular energy in the form of ATP. Patients with genetic OXPHOS disorders form the largest group of inborn errors of metabolism. Unfortunately, there is still a lack of efficient therapies for these disorders other than management of symptoms. Developing therapies has been complicated because, although the total group of OXPHOS patients is relatively large, there is enormous clinical and genetic heterogeneity within this patient population. Thus there has been a lot of interest in generating relevant mouse models for the different kinds of OXPHOS disorders. The most common treatment strategies tested in these mouse models have aimed to up-regulate mitochondrial biogenesis, in order to increase the residual OXPHOS activity present in affected animals and thereby to ameliorate the energy deficiency. Drugs such as bezafibrate, resveratrol and AICAR target the master regulator of mitochondrial biogenesis PGC-1α either directly or indirectly to manipulate mitochondrial metabolism. This review will summarize the outcome of preclinical treatment trials with these drugs in mouse models of OXPHOS disorders and discuss similar treatments in a number of mouse models of common diseases in which pathology is closely linked to mitochondrial dysfunction. In the majority of these studies the pharmacological activation of the PGC-1α axis shows true potential as therapy; however, other effects besides mitochondrial biogenesis may be contributing to this as well.
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia.
authors.forename: J C
authors.initials: JC
authors.lastname: Komen
authors.forename: D R
authors.initials: DR
authors.lastname: Thorburn
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology*; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000378:metabolism; D063269:Mitochondrial Turnover / Q000187:drug effects*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077185:Resveratrol; D012265:Ribonucleotides / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000187:drug effects / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012265:Ribonucleotides; D013267:Stilbenes; D014157:Transcription Factors; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C031143:AICA ribonucleotide; D000077185:Resveratrol; D001629:Bezafibrate
keywords: AICAR; PGC-1α; bezafibrate; mitochondria; mitochondrial biogenesis; mitochondrial disease; mouse models; oxidative phosphorylation; resveratrol